Peramivir binding affinity with influenza A neuraminidase and research on its mutations using an induced-fit docking approach

ABSTRACT

Influenza A virus (IAV) has caused epidemic infections worldwide, with many strains resistant to inhibitors of a surface protein, neuraminidase (NA), due to point mutations on its structure. A novel NA inhibitor named peramivir was recently approved, but no exhaustive computational research regarding its binding affinity with wild-type and mutant NA has been conducted. In this study, a thorough investigation of IAV-NA PDB entries of 9 subtypes is described, providing a list of residues constituting the protein-ligand binding sites. The results of induced-fit docking approach point out key residues of wild-type NA participating in hydrogen bonds and/or ionic interactions with peramivir, among which Arg 368 is responsible for a peramivir-NA ionic interaction. Mutations on this residue greatly reduced the binding affinity of peramivir with NA, with 3 mutations R378Q, R378K and R378L (NA6) capable of deteriorating the docking performance of peramivir by over 50%. 200 compounds from 6-scaffolds were docked into these 3 mutant versions, revealing 18 compounds giving the most promising results. Among them, CMC-2012-7-1527-56 (benzoic acid scaffold, IC50 = 32 nM in inhibitory assays with IAV) is deemed the most potential inhibitor of mutant NA resisting both peramivir and zanamivir, and should be further investigated.

KEYWORDS:

• Influenza A virus
• neuraminidase
• inhibitor
• peramivir
• in silico mutation
• induced-fit docking
• binding affinity

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary Material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2019.1679248

Additional information

Funding

This research is funded by Vietnam National University Ho Chi Minh City (VNU) under Grant number [C2018-44-01/HĐ-KHCN] (to Minh-Tri Le) and by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) under the grant number [106-YS.05-2015.31] (to Khac-Minh Thai) and [108.05-2017.12] (to Minh-Tri Le).